There are many circumstances in which it is desirable to deliver drugs to an individual at a controlled rate, so as to extend the period of action of the drug over a convenient time span. The most common examples of this are decongestants and allergy medicines, in which it is very convenient for individuals to take a single pill every twelve hours, as opposed to having to take a pill every two to four hours. Another example is the use of timed-release formulations of pain relievers. Such formulations allow a convenient way for sufferers of chronic pain, such as arthritis or back pain, to lead more normal lives without the necessity of taking pills on a frequent basis. The lack of the necessity of taking pills on a frequent basis is of particular benefit because it may allow the individual to sleep through an entire night without pain or disturbance.
A number of means of achieving the controlled release of drugs have been utilized. Probably the most common means is to put coatings on small particles of the drug. When the drug is in the digestive tract, this coating gradually dissolves, releasing the drug. If one uses coatings of different thicknesses, or coatings have differing rates of dissolution, it is possible to deliver the drug at a number of different rates, thereby achieving a more steady physiological concentration over a long period of time. Multiple coatings may also be used, or coatings responsive to varying pH conditions in the body. Other methods besides coating drug particles have been used to achieve controlled release. These include embedding the drug in a polymer matrix or a vesicle, such as a liposome, which may be biodegradable, and relying on the diffusion of the drug from these matrices. By varying the polymer composition, the delivery rate may be varied.
Polymers used as drug delivery systems which release the drug upon biodegradation under appropriate conditions are disclosed in U.S. Pat. Nos. 6,274,175; 6,251,430; 5,955,068; 5,407,682; 5,330,768; 5,316,774; 5,026,821; 4,489,056; and 4,346,709; and U.S. patent publication US2002/0064546A1.
A number of patents disclose the use of cleavable conjugates of drugs with polymers or other molecules. Typically the bonds are easily hydrolyzable under mild conditions. See, e.g., U.S. Pat. Nos. 6,300,458; 6,214,966; 5,877,158; 5,827,925; 5,654,381; 5,563,250; 5,498,729; 5,455,027; 5,317,077; 5,306,809; 5,258,453; 5,216,115; 5,144,011; 5,017,693; 4,891,225; 4,842,868; and 4,386,026.
A significant problem in current controlled release technology for drugs is that it may be circumvented in a fairly straightforward fashion. This problem most frequently arises for analgesics. For example, there is currently a timed-release formulation of oxycodone (marketed under the trade name OXYCONTIN®) that is intended to provide for long-term pain relief when swallowed in a controlled release formulation. If the capsule or tablet is simply ground or chewed up thoroughly to destroy the microencapsulation around the drug, and then swallowed, all of the oxycodone is immediately available, and the individual receives a morphine-like “high.” The fact that repeated use of high dosages of oxycodone may lead to addiction, coupled with the ease with which the controlled release mechanism of this drug may be circumvented, has unfortunately led to widespread abuse of the drug, to the point that there have been calls for its use to be banned or severely restricted.
While the purposeful circumvention of a timed-release mechanism is an obvious problem for narcotic analgesics, it may also become a problem for other drugs. In particular, there are drugs that have a relatively narrow window of safety—drugs for which the difference between an optimal dose and an overdose is not extremely large. Presentation of such drugs in a timed-release formulation that provides for their gradual delivery is an obvious solution to this problem; however, there exists the possibility of an accidental circumvention of the time-release process that can have disastrous consequences. In particular, there is an ever-increasing population of the elderly who take large numbers of a wide variety of pills, many of which have differing instructions for use. If a time-release formulation meant to be swallowed is mistaken for a type of tablet meant to be chewed, a potentially life-threatening dosage of drug may be rapidly delivered.
There is, therefore, a need for timed-release formulations for drugs allowing release to be precisely controlled, and a need for such formulations which are not easily circumventable.
All publications referred to herein are incorporated by reference to the extent not inconsistent herewith.